Double‐transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations

British Journal of Pharmacology - Tập 163 Số 3 - Trang 546-555 - 2011
Jörg König1, Oliver Zolk1, Katrin Singer1, Christiane Hoffmann1, Martin F. Fromm1
1Institute of Experimental and Clinical Pharmacology and Toxicology, Universität of Erlangen‐Nürnberg, Fahrstr. 17, Erlangen, Germany

Tóm tắt

BACKGROUND AND PURPOSE The organic cation transporters 1 (OCT1) and 2 (OCT2) mediate drug uptake into hepatocytes and renal proximal tubular cells, respectively. Multidrug and toxin extrusion protein 1 (MATE1) is a major component of subsequent export into bile and urine. However, the functional interaction of OCTs and MATE1 for uptake and transcellular transport of the oral antidiabetic drug metformin or of the cation 1‐methyl‐4‐phenylpyridinium (MPP+) has not fully been characterized.EXPERIMENTAL APPROACH Single‐transfected Madin‐Darby canine kidney (MDCK) cells as well as double‐transfected MDCK‐OCT1‐MATE1 and ‐OCT2‐MATE1 cells were used to study metformin and MPP+ uptake into and transcellular transport across cell monolayers, along with their concentration and pH dependence.KEY RESULTS Cellular accumulation of MPP+ and metformin was significantly reduced by 31% and 46% in MDCK‐MATE1 single‐transfected cells compared with MDCK control cells (10 µM; P < 0.01). Over a wide concentration range (10–2500 µM) metformin transcellular transport from the basal into the apical compartment was significantly higher in the double‐transfected cells compared with the MDCK control and MDCK‐MATE1 monolayers. This process was not saturated up to metformin concentrations of 2500 µM. In MDCK‐OCT2‐MATE1 cells basal to apical MPP+ and metformin transcellular translocation decreased with increasing pH from 6.0 to 7.5.CONCLUSIONS AND IMPLICATIONS Our data demonstrate functional interplay between OCT1/OCT2‐mediated uptake and efflux by MATE1. Moreover, MATE1 function in human kidney might be modified by changes in luminal pH values.

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Thông tin
Thông tin xuất bản

British Journal of Pharmacology

Tập 163 Số 3

546-555

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